Technical Field
The present invention stands in the fields of pharmacy, medicine, chemical and biotechnology. More specifically, the present invention described a novel modified peptide acting as cannabinoid (CB) receptors-ligands, specially CB1 and/or CB2, and/or modulator of its activity; they are also described in one kit and one in vitro process for evaluating the binding to CB receptors, uses and pharmaceutical composition for modulating the CB receptors activity.
Prior Art
The cannabinoid system, comprising the cannabinoid receptors (CB), CB1 and CB2 and their endogenous ligands, acts in the ingestion control of food and in the energy metabolism and it is widely expressed in the brain, including cortex, hippocampus, tonsil, pituitary and hypothalamus. CB receptors, particularly CB1, were already identified in several peripheral organs and tissues, including thyroid gland, adrenal gland, reproductive organs, adipose tissue, liver, muscles and gastrointestinal tract.
Several compounds were already detected in the art having modulation activity of this receptor and, between them, the compound Rimonabant—drug used to reduce loss and waist thinning and that was widely use in the pharmaceutical market. However, this compound was subsequently associated to the occurrence of psychiatric diseases in humans, mainly by crossing the hematoencenphalic layer, being then removed from the worldwide market. The hematoencephalic barrier is a barrier highly selective protecting the brain preventing the input, by the system circulation, from potentially harmful substances to the central nervous system. Thus, there is a need in the art of obtaining novel compounds that may modulate the activity of cannabinoid receptors, preferably of the CB1 and/or CB2 receptor, however without having a passage of the same by the hematoencephalic barrier.
The present invention described a novel non-natural peptide, which shows surprisingly results regarding its activity, more especially regarding its use and/or its modulation activity of cannabinoid receptors. The peptide of the present invention, further, has the advantage of being particularly useful for modulating the CB receptors activity and in the treatment of metabolic disorders as, for example, reduce obesity, having the additional advantage of not crossing the hematoencephalic barrier, as show the researches results performed by the inventors.
The search for records disclosed documents only partially relevant for the present invention. Such documents are described bellow, being these place here only with the object of serving the base to the current state of the art, once anyone anticipated or suggests any one of the objects of the present invention.
The document US 2007/213302 shows interaction compounds with CB1 receptor, consisting of pyrazoles and its pharmaceutically acceptable salts acting as antagonists or inverse agonists of the CB1 receptor. The present invention differs from the said document, among other reasons, by showing a novel non-natural peptide, that does not comprise pyrazoles or its salts, and such results are surprisingly, especially regarding the interaction with cannabinoids receptors, facts not described neither suggested in the said document.
The document WO 2011/011847 discloses the use of the hemopressin to treat obesity in a subject and is further disclosed that hemopressin é a compound binding efficiently to the CB1 receptor and does not cross the hematoencephalic barrier. The present invention differs from this document, among other reasons, by showing a novel non-natural peptide, derived from angiotensin conversion enzyme. However, the peptide of the invention is not similar to hemopressin. In addition, the tests results performed by the inventors showed surprisingly, especially regarding the interaction with cannabinoid receptors, facts not described neither suggested in the said document.
Some studies showed by the present inventors in “Novel Natural Peptide Substrates for Endopeptidase 24.15 Neurolysin, and Angiotensin-converting Enzyme” (Vanessa Rioli, Fabio C. Gozzo, Andrea S. Heimann, Alessandra Linardi, José E. Krieger, Claudio S. Shida, Paulo C. Almeida, Stephen Hyslop, Marcos N. Eberlin, Emer S. Ferro; 7 de Março de 2003) demonstrated a efficient technique of “screening” novel peptides, which was used in the present invention to detect a peptide with natural sequence for specific proteins regulation. However, any utility regarding the cannabinoid system was found with this natural peptide. The present invention differs from this document, among other reasons, by showing a novel non-natural peptide, which results showed surprisingly, especially regarding the interaction with cannabinoid receptors, fact not described neither cited in any document of the state of the art.
The present invention provides a novel non-natural peptide, that among other functions and uses is ligand for CB receptors and that does not have the inconvenient derived from the interaction with the hematoencephalic layer—and that further provides several useful technical effects. In special, it is disclosed in the present invention a novel non-natural peptide with sequence SeqID:1 and/or with sequence with similarity of, at least, 70% related to the same. The non-natural peptide of the invention is particularly useful as cannabinoid receptors-ligand and/or as modulator of the CB receptors activity. The non-natural peptide of the invention, despite being in general a ligand in a higher level than those known in the art, does not interact with the hematoencephalic barrier, providing additional advantages in the therapeutic use in mammalians.
It follows from the research literature, there were not found documents anticipating or suggesting teachings of the present invention, such that the solution here proposed, to the inventors eyes, has novelty and inventive activity against the state of the art.